Method of producing pharmaceutic ally



United States Patent 3,040,049 METHOD OF PRODUCING PHARMACEUTICALLYACTIVE TROPINYLETHERS August F. Harms, Amsterdam, Netherlands, assignorto N.V. Koninklijke Pharmaceutische Fabrieken v/h Brocades-Stheeman &Pharmacia, Meppel, Netherlands, a corporation of the Netherlands NoDrawing. Filed June 2, 1958, Ser. No. 738,956 Claims priority,application Netherlands May 31, 1957 1 Claim. (Cl. 260-292) Thisinvention relates to the production of pharmaceutically activetropinylethers of the general formula Ar; CHz-CH CH2 A1: CH CH CHg inwhich Ar and Ar are substituted or unsubstituted phenyl groups as wellas salts and quaternary ammonium compounds thereof. Examples of saltsare the hydrobromide, the hydrochloride, the sulphate and the methanesulphonate.

Various compounds of the above mentioned structure are known. Thus U.S.*Patent 2,595,405 describes the unsubstituted compound, while US. Patent2,706,198 and British Patents 708,911, 769,282 and 773,290 describe anumber of compounds substituted in a phenyl group. The said patentslikewise mention a number of methods of preparing said compounds.Substances having the above formula have pronounced atropine-likeproperties as well as a strong antihistaminic activity.

I have now found that compounds having an appreciably stronger activitycan be obtained if at least one of the phenyl nuclei possesses an alkylsubstituent in at least one of the ortho positions. According to theinvention, therefore, compounds of the above general formula areprepared in a manner known for similar compounds, in which compounds atleast one of the groups Ar or Ar is substituted in at least one of theortho positions by an alkyl group having at most 6 carbon atoms, the twogroups containing no other substituents.

It is true that US. Patent 2,706,198 discloses compounds of the generalformula:

in which R and R may represent i.=a. low 'alkyl groups, but the alkylsubstituted compounds described in said patent all contain one or moresubstituents in the paraor meta-position in the phenyl nuclei. Inaddition it appears from the patent that primarily the para halogensubstituted compounds are considered of importance. I have found thatparticularly the monoortho-methyl substituted compound has a verypronounced atropine-like activity, which many times exceeds the activityof the corresponding unsubstituted compound as Well as the activity ofthe mono-meta and mono-para methyl-substituted compound. In addition thetoxicity is of the same order of magnitude or even smaller than that ofthe isomeric compounds or that of the unsubstituted compound, so thatthe therapeutic width of the mono-ortho-methyl compound is appreciablylarger than that of the corresponding compounds not having the methylgroup or having it in a different position in the phenyl nucleus.

The subjoined table lists the pharmacological test results obtained incomparative experiments applied to the isolated intestine of cavies bymeans of compounds sub- Spasmolytic activity Toxicity 50 in mg. per kg.of mouse in the ease of an intravenous injection) Substituent HZ AntiBaOlz Anti Acetylch, activity HBr sulphateatropine In addition to thestrong atropine-like activity described above the compounds according tothe invention have the property that they entirely eliminate tremorscreated by the administration of 1,4-dipyrrolidinobutyn-2, as doesatropine (C. M. Everett, Nature 177, 1238 (1956)).

If in mice 25 mg./kg. 1,4-dipyrrolidinobutyn-2 was injected theeffective dose in at least 50% of the mice (ED in the case of asubcutaneous injection amounted to 2.5 mg./kg. mouse for the 2 methylcompound and to 21 mg./kg. mouse for the 2 tertiary butyl compound.

Also in this respect the 2 methyl benzhydryltropinylother again appearsto have exceptional properties.

The compounds according to the application can be prepared in variousWays. According to the most usual method a compound of the formula:

is reacted with a compound of the formula:

CH2'CHCH2 B-OH NCH GH2-CH-OH2 in which A represents a halogen atom andBan OH group or A an OH group and B a halogen atom or an OH group. Ifone of the symbols A and B represents a halogen atom and the other an OHgroup the reaction is generally carried out with the addition of anoxygen binding sub stance. If A is the halogen atom it is also possibleto carry out the reaction with an excess of the amino alcohol withoutthe addition of another oxygen binding substance. It is possible, forexample, to obtain the compounds according to the application by heatingone equivalent of the desired substituted benzhydryl with twoequivalents of the amino alcohol, the addition of a solvent being notnecessary.

Preferably, however, a compound is reacted with a compound CHz-CHCH2HO-OH NCH3 CH2CH OH: in the presence of an organic sulphonic acid suchas ptoluenesulphonic acid the reaction mixture being heated. Theinvention will be elucidated with reference to the following examples:

Example I 21.6 grams of Z-methylbenzhydrylchloride (0.1 mol) are heatedwith 25.8 grams of tropinol (0.2 mol) at a temperature of from 100150 C.for 15-30 minutes. A two layer system will form, the lower layer ofwhich solidifies upon slight cooling. After cooling of the reactionmixture 100-15O cc. of ether are added, in which the liquid upper layerwill dissolve. After separating the ether layer 150 cc. of water andsubsequently 25 cc. of 40% hydrobromic acid are added thereto. Theprecipitate consisting of 2 methylbenzhydryl tropinyl ether hydrobromideis separated by filtration, washed with ether and subsequently withwater and is thereupon dried.

The yield of the said product amounts to 14 grams (45%). Afterpurification by crystallization the compound melts at 222224 C.

Example ll Tropinolis converted into chlorotropane by means of thionylchloride. "One mol of chlorotropane together with one mol of 2methylbenzhydrol is heated in the presence of sodamide as an acidbinding substance at a temperature-of from IOU-150 C. for 15-30 minutes.

The reaction mixture is Worked up as described in Example I. Since thechance of quaternary salts forming is much slighter here than in thepreceding method the yield is appreciably larger; it amounts to 60%.Melting point after crystallization is 221-223 'C.

Example III To 1.0 mol of orthomethylbenzhydrol 1.1 mol of tropinol areadded. The mixture is heated to 50-60 C. until a homogeneous melt isobtained. To this melt 1.15 mol of p-toluenesulphonic acid are addedowing to which the temperature rises to 90100 C. Subsequently themixture is heated at a temperature of 130-150 C. under reduced pressurefor 4 to 5 hours. After cooling the mixture is taken up in a mixture ofdiluted lye and ether. The layer of ether is separated out and treatedwith a dilute aqueous HBr-solution. The hydrobromide of 2-methylbenzhydryltropinylether separates out as an oil which soonsolidifies.

The solid substance is isolated and crystallized from acetone or from amixture of acetone and ether. The yield is 75%. Melting point is 223224C.

Example IV In the same manner as described in Example III thehydrobromide of Z-ethylbenzhydryl tropinyl ether is prepared fromortho-ethyl benzhydrol, tropinol and p-toluene sulphonic acid. Meltingpoint after crystallization is 180 C. Yield 67%.

4 Example V In the same manner as described in Example III the tropinyl2,2'-dimethyl benzhydryl tropinyl ether is prepared from2,2-dimethylbenzhydrol. The melting point of the hydrobromide is 194 C.The yield is Example VI formula Al; CH2-CH--CH HC'3-O(|3H N-CH Al: H2- H0112 which comprises reacting a compound of the general formula Al1 I-I(7A with a compound of the general formula CH2CH-OHq BCH N-CHQ Hr-CHwherein Ar; and Ar are phenyl groups of which at least one issubstituted in at least one of the ortho-positions by an alkyl groupcontaining at most 6 carbon atoms, while both groups Ar and Ar are freefrom other substituents in an ortho-position and are free fromsubstituents in any position other than the ortho-position, A is ahydroxyl group, B is a hydroxyl group, and the reaction is carried outin the presence of toluene sulphonic acid.

References Cited in the file of this patent UNITED STATES PATENTSWeijlard et al Apr. 12, 1955 Nield et al. Feb. 19, 1957

